Vidar R. Jensen

Neurological dysfunctions in mice expressing different levels of the Q/R site–unedited AMPAR subunit GluR–B

We generated mouse mutants with targeted AMPA receptor (AMPAR) GluR–B subunit alleles, functionally expressed at different levels and deficient in Q/R–site editing. All mutant lines had increased AMPAR calcium permeabilities in pyramidal neurons, and one showed elevated macroscopic conductances of these channels. The AMPAR–mediated calcium influx induced NMDA–receptor–independent long–term potentiation (LTP) in hippocampal pyramidal cell connections. Calcium–triggered neuronal death was not observed, but mutants had mild to severe neurological dysfunctions, including epilepsy and deficits in dendritic architecture. The seizure–prone phenotype correlated with an increase in the macroscopic conductance, as independently revealed by the effect of a transgene for a Q/R–site–altered GluR–B subunit. Thus, changes in GluR–B gene expression and Q/R site editing can affect critical architectural and functional aspects of excitatory principal neurons.

Metal−Phosphine Bond Strengths of the Transition Metals: A Challenge for DFT†

Previous promising tests of the new M06 family of functionals in predicting ruthenium-metal phosphine bond dissociation energies (Zhao, Y.; Truhlar, D. G. Acc. Chem. Res. 2008, 41, 157) have been extended to a series of phosphine complexes of chromium, molybdenum, nickel, and ruthenium for which relevant experimental data are available. In addition to the M06 family of functionals, bond dissociation enthalpies have been calculated using a selection of density functionals and hybrid functionals based on the generalized gradient approximation (GGA), and with or without an empirical term (i.e., DFT-D) accounting for long-range dispersion. For the ruthenium complexes, second-order Møller-Plesset perturbation theory (MP2) has also been applied. Electrostatic and nonelectrostatic solvent effects have been estimated using the polarizable continuum model (PCM), allowing for comparison with experimental data obtained for dissociation reactions in organic solvents. Whereas the GGA and hybrid-GGA functionals grossly underestimate the absolute metal-phosphine bond enthalpies, with mean unsigned errors (MUEs) for a set of 10 phosphine dissociation reactions in the range 13-27 kcal/mol, the recently developed DFT-based methods for inclusion of attractive noncovalent interactions and dispersion (the DFT-D and M06 functionals) dramatically improve upon the situation. The best agreement with experiment is observed for BLYP-D (MUE = 2.2 kcal/mol), and with the exception for M06-2X, all these methods provide MUEs well below 5 kcal/mol, which should be sufficient for a broad range of applications. The improvements in predicted relative bond enthalpies are less convincing, however. In several cases the GGA and hybrid-GGA functionals are better at reproducing substitution effects than the DFT-D and M06 methods.

Simple and Highly Z-Selective Ruthenium-Based Olefin Metathesis Catalyst

A one-step substitution of a single chloride anion of the Grubbs-Hoveyda second-generation catalyst with a 2,4,6-triphenylbenzenethiolate ligand resulted in an active olefin metathesis catalyst with remarkable Z selectivity, reaching 96% in metathesis homocoupling of terminal olefins. High turnover numbers (up to 2000 for homocoupling of 1-octene) were obtained along with sustained appreciable Z selectivity (>85%). Apart from the Z selectivity, many properties of the new catalyst, such as robustness toward oxygen and water as well as a tendency to isomerize substrates and react with internal olefin products, resemble those of the parent catalyst.

IκB Kinase/Nuclear Factor κB-Dependent Insulin-Like Growth Factor 2 (Igf2) Expression Regulates Synapse Formation and Spine Maturation via Igf2 Receptor Signaling

Alterations of learning and memory in mice with deregulated neuron-specific nuclear factor κB (NF-κB) activity support the idea that plastic changes of synaptic contacts may depend at least in part on IκB kinase (IKK)/NF-κB-related synapse-to-nucleus signaling. There is, however, little information on the molecular requirements and mechanisms regulating this IKK/NF-κB-dependent synapse development and remodeling. Here, we report that the NF-κB inducing IKK kinase complex is localized at the postsynaptic density (PSD) and activated under basal conditions in the adult mouse brain. Using different models of conditional genetic inactivation of IKK2 function in mouse principal neurons, we show that IKK/NF-κB signaling is critically involved in synapse formation and spine maturation in the adult brain. IKK/NF-κB blockade in the forebrain of mutant animals is associated with reduced levels of mature spines and postsynaptic proteins PSD95, SAP97, GluA1, AMPAR-mediated basal synaptic transmission and a spatial learning impairment. Synaptic deficits can be restored in adult animals within 1 week by IKK/NF-κB reactivation, indicating a highly dynamic IKK/NF-κB-dependent regulation process. We further identified the insulin-like growth factor 2 gene (Igf2) as a novel IKK/NF-κB target. Exogenous Igf2 was able to restore synapse density and promoted spine maturation in IKK/NF-κB signaling-deficient neurons within 24 h. This process depends on Igf2/Igf2R-mediated MEK/ERK activation. Our findings illustrate a fundamental role of IKK/NF-κB–Igf2–Igf2R signaling in synapse formation and maturation in adult mice, thus providing an intriguing link between the molecular actions of IKK/NF-κB in neurons and the memory enhancement factor Igf2.

Synthesis and Stability of Homoleptic Metal(III) Tetramethylaluminates

Whereas a number of homoleptic metal(III) tetramethylaluminates M(AlMe(4))(3) of the rare earth metals have proven accessible, the stability of these compounds varies strongly among the metals, with some even escaping preparation altogether. The differences in stability may seem puzzling given that this class of metals usually is considered to be relatively uniform with respect to properties. On the basis of quantum chemically obtained relative energies and atomic and molecular descriptors of homoleptic tris(tetramethylaluminate) and related compounds of rare earth metals, transition metals, p-block metals, and actinides, multivariate modeling has identified the importance of ionic metal-methylaluminate bonding and small steric repulsion between the methylaluminate ligands for obtaining stable homoleptic compounds. Low electronegativity and a sufficiently large ionic radius are thus essential properties for the central metal atom. Whereas scandium and many transition metals are too small and too electronegative for this task, all lanthanides and actinides covered in this study are predicted to give homoleptic compounds stable toward loss of trimethylaluminum, the expected main decomposition reaction. Three of the predicted lanthanide-based compounds Ln(AlMe(4))(3) (Ln = Ce, Tm, Yb) have been prepared and fully characterized in the present work, in addition to Ln(OCH(2)tBu)(3)(AlMe(3))(3) (Ln = Sc, Nd) and [Eu(AlEt(4))(2)](n). At ambient temperature, donor-free hexane solutions of Ln(AlMe(4))(3) of the Ln(3+)/Ln(2+) redox-active metal centers display enhanced reduction to [Ln(AlMe(4))(2)](n) with decreasing negative redox potential, in the order Eu ≫ Yb ≫ Sm. Whereas Eu(AlMe(4))(3) could not be identified, Yb(AlMe(4))(3) turned out to be isolable in low yield. All attempts to prepare the putative Sc(AlMe(4))(3), featuring the smallest rare earth metal center, failed.

An evolutionary algorithm for de novo optimization of functional transition metal compounds.

Development of functional inorganic and transition metal compounds is usually based on ad hoc qualified guesses, with computational methods playing a lesser role than in drug discovery. A de novo evolutionary algorithm (EA) is presented that automatically generates transition metal complexes using a search space constrained around chemically meaningful structures assembled from three kinds of fragments: a part shared by all structures and typically containing the metal center itself, one or several parts consisting of ligand skeletons, and unconstrained parts that may grow and vary freely. In EA optimizations, using a cost-efficient fitness function based on a linear quantitative structure-activity relationship model for catalytic activity, we demonstrate the capabilities of the method by retracing the transition from the first-generation, phosphine-based Grubbs olefin metathesis catalysts to second-generation catalysts containing N-heterocyclic carbene ligands instead of phosphines. Moreover, DFT calculations on selected high-fitness, last-generation structures from these evolutionary experiments suggest that, in terms of catalytic activity, the structures arrived at by virtual evolution alone compare favorably with existing, highly active catalysts. The structures from the evolution experiments are, however, complex and probably difficult to synthesize, but a set of manually simplified variations thereof might form the leads for a new generation of Grubbs catalysts.

An investigation of the quantum chemical description of the ethylenic double bond in reactions: II. Insertion of ethylene into a titanium–carbon bond

Insertion of ethylene into the Ti–methyl bond in TiH2CH+3 is chosen as a model reaction for investigating the performance of a range of contemporary quantum chemical models in polymerization studies. Basis set effects are investigated at the self‐consistent‐field level, covering Hartree–Fock, pure DFT, and hybrid DFT. In agreement with findings in part I of this study, the basis set sensitivity of ethylene is shown to introduce a bias in computed energetics, amounting to 2–3 kcal/mol when DZP bases are used to compute the overall heat of monomer insertion. The geometry of stationary points relevant to the insertion reaction is determined using hybrid density functional theory. Based on these structures, the energy profile of the insertion reaction is computed using a range of popular quantum chemical approximations. The methods include Hartree–Fock and Møller–Plesset (MP) perturbation theory up through the fourth order in spin‐restricted, spin‐unrestricted, and spin‐projected formalisms. Furthermore, configuration‐interaction‐based methods are included, of which the top level method is singly and doubly excited coupled clusters with a perturbative estimate of the contribution from triply excited configurations added [CCSD(T)]. The performance of the methods just mentioned, as well as three pure density functional and three hybrid density functional methods, are compared with respect to “best” relative energies, defined through extrapolation of CCSD(T) correlation energies according to the PCI scheme of Siegbahn and coworkers. Even though the MP series show poor convergence, spin‐projected MP2, as well as two pure DFT methods (BPW91, BP86) and PCI‐78 based on the MCPF method, show similar and very good agreement with best relative energies for the insertion reaction. © 1998 John Wiley & Sons, Inc. J Comput Chem 19: 947–960, 1998

Evolutionary de novo design of phenothiazine derivatives for dye-sensitized solar cells

Traditional approaches for improving the photovoltaic performance of dye-sensitized solar cells (DSSCs) have mainly relied on judicious molecular design and device level modifications. Such schemes, however, are bound by costly and time-consuming synthesis procedures. In this paper, we demonstrate the efficacy of an alternative approach based on in silico evolutionary de novo design of novel dye structures with improved DSSC power conversion efficiency (PCE) values. Because the PCE, cannot as yet be directly computed from first principles, the evolutionary fitness function utilizes predictive structure–property relationship (QSPR) models calibrated from empirical data. Our design approach is applied to phenothiazine-based dye sensitizers. The chemical structure space is explored using a genetic algorithm that systematically assembles molecules from fragments in a synthetically tractable manner. Five novel phenothiazine dyes are proposed using our approach where all have predicted PCE values above 9%.

Automated design of realistic organometallic molecules from fragments.

A method for the automated generation of realistic, synthetically accessible transition metal and organometallic complexes is described. Computational tools were designed to generate molecular fragments, preferably harvested from libraries of existing, stable compounds, to be used as building blocks for the construction of new molecules. These fragments are enriched with information about the number and type of possible connections to other fragments and are stored in library files. When connecting fragments in the subsequent building process, compatibility matrices, which define the connection rules between fragments, are used to delineate organometallic fragment spaces from which molecules can be generated in an automated fashion. The approach is flexible and allows ample structural variation at the same time as the combination of known fragments is easily restrained to avoid generation of exotic and unrealistic substructures and molecules. The method was tested in the generation of ruthenium complexes, with a given coordination environment, which can serve as candidates in catalyst development. The results demonstrate that molecules generated with the described method do not contain exotic arrangements of atoms and are by far more realistic than those obtained by the application of valence rules alone.

Neutral Nickel Oligo‐ and Polymerization Catalysts: The Importance of Alkyl Phosphine Intermediates in Chain Termination

An unconventional chain termination reaction has been explored for the SHOP (Shell higher olefin process)-type, anilinotropone, and salicylaldiminato nickel-based oligo- and polymerization catalysts by using density functional theory (DFT). Starting from the tetracoordinate alkyl phosphine complex, the termination reaction was found to involve a rearrangement of the alkyl chain to form a pentacoordinate β-agostic complex, β-hydride elimination, and olefinic chain dissociation and to compete with propagation at sufficiently high phosphine concentration and/or basicity. It provides the first complete and convincing mechanistic rationale for the decreasing chain lengths observed upon increasing phosphine concentration and basicity. The unconventional reaction was found to be a major termination pathway for the SHOP-type catalyst and is very unlikely to lead to branching and olefin isomerization, which is critical for explaining why the SHOP catalyst, in contrast to the anilinotropone and salicylaldiminato catalysts, tends to lead to the oligomerization of ethylene to form linear α-olefins. Based on our results we have proposed a new and extended catalytic cycle for the SHOP-type ethylene oligomerization catalyst. Finally, the importance of the new termination reaction for the SHOP-type catalyst suggests that this reaction may also operate with other ethylene oligomerization nickel catalysts. This prediction was confirmed for a pyrazolonatophosphine catalyst, for which the new termination route was found to be even more facile, which explains the short oligomers produced by this catalyst.